Cannabinoid type 2 receptor (CB2R) distribution in dermatomyositis skin and peripheral blood mononuclear cells (PBMCs) and in vivo effects of LenabasumTM

Spandana Maddukuri,Muhammad M Bashir,Nithin Reddy,Victoria P Werth,Josef Symon S Concha,Christina Bax,Kristen L Chen,Jay Patel,De Anna Diaz,Maria Wysocka,Majid Zeidi,Madison Grinnell,Joyce Okawa,Barbara White,Adarsh Ravishankar,Yubin Li

doi:10.1186/s13075-021-02665-x

Abstract

BackgroundLenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM.MethodsImmunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations.ResultsAfter 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β.ConclusionOur findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.

Highlights

Dermatomyositis (DM) is a rare chronic systemic autoimmune disease that primarily affects the skin, muscle, and lungs [1]
cannabinoid type 2 receptor (CB2R) expression is increased in dermatomyositis skin compared to healthy control skin To evaluate CB2R expression in DM skin, we first utilized immunofluorescence (IF) staining and observed increased expression of the CB2R marker in DM skin compared to healthy controls (HC) skin (Fig. 1a, red)
The immune populations are listed here in decreasing order according to percent composition of the inflammatory infiltrate: CD14+ macrophages (Mac), CD11c+ myeloid dendritic cells, CD14+CD16+ Mac, CD4+ T cells, MAC387+ Mac, mast cells, CD8+ T cells, FOXP3+ T cells, Phosphorylated stimulator of interferon genes (pSTING)+ Mac, BDCA2+ Plasmacytoid dendritic cell (pDC), CD56hi NK cells, and B cells [22]

Summary

Introduction

Dermatomyositis (DM) is a rare chronic systemic autoimmune disease that primarily affects the skin, muscle, and lungs [1]. They are often ineffective and cause adverse drug reactions [6,7,8]. Systemic therapies for antimalarial-refractory DM include glucocorticoids, immunosuppressives, and intravenous immunoglobulin (IVIG) but are associated with numerous side effects [8]. The decreased QoL of DM patients combined with the inadequacy of current treatments highlight the therapeutic need for effective and safer treatment options. Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM

Objectives

Methods

Results

Discussion

Conclusion